Current medicinal chemistry最新文献

Background: Sarcopenia, an aseptic chronic inflammatory disease, is a complex and debilitating disease characterized by the progressive degeneration of skeletal muscle. PANoptosis, a novel proinflammatory programmed cell death pathway, has been linked to various diseases. However, the precise role of PANoptosis-related features in sarcopenia remains uncertain.

Methods: According to the intersection of differentially expressed genes (DEGs) in the sarcopenia dataset GSE167186 and the PANoptosis gene set, we classified patients into PANoptosis-related subtypes (PANRS) using consensus clustering. The DEGs of PANRS were intersected with weighted gene co-expression network analysis (WGCNA). Proteinprotein interaction network and cytoHubba algorithms were employed to further identify potential genes related to PANoptosis. The most characteristic genes were selected using LASSO regression and validated by ROC curve analysis, followed by relevant immune infiltration analysis. Additionally, small-molecule drug screening was performed using Cmap. The relative expression levels of hub genes in sarcopenia were confirmed by PCR. Finally, single-cell analysis and GSEA were used to examine the distribution and function of hub genes.

Results: Thirty-five candidate genes were identified through WGCNA and PANRS. Machine learning and ROC curve analysis revealed three core genes: LTBP2, ETS2, and H3.3B, all of which were up-regulated in patients with sarcopenia (p<0.01). Immune infiltration analysis indicated that these three diagnostic genes were linked to the activation of NK cells and macrophages. Single-cell analysis demonstrated that LTBP2 was mainly localized in fibroblasts, while ETS2 and H3.3B exhibited a uniform distribution. Enrichment analysis indicated that the three hub genes were predominantly associated with the inhibition of energy metabolism.

Conclusion: In this study, the hub genes LTBP2, ETS2, and H3.3B associated with PANoptosis in sarcopenia were successfully identified through a combination of bioinformatics and experimental verification methods. This establishes a foundation for new candidate diagnostic and therapeutic targets for sarcopenia.

Objective: LGALS3BP exhibits differential expression in various types of tumors. This study aimed to analyze its potential diagnostic and prognostic value in Triple- negative Breast Cancer (TNBC).

Methods: We conducted a comprehensive analysis of LGALS3BP's differential expression and its association with patient survival outcomes using data from public databases. To further validate these findings, Immunohistochemistry (IHC) experiments were performed to confirm the differential expression of LGALS3BP protein in TNBC. Additionally, we also investigated the relationship among LGALS3BP, tumor immune infiltration, and drug sensitivity.

Results: Results indicated LGALS3BP to be significantly upregulated in TNBC, with its high expression correlating with improved survival outcomes. Furthermore, LGALS3BP expression correlated with immune cell infiltration. Notably, high LGALS3BP expression may confer a greater likelihood of benefiting from immunotherapy.

Conclusion: LGALS3BP may serve as a diagnostic and prognostic biomarker for TNBC.

Introduction: Melanoma is one of the most dangerous and common types of cancer in humans. In order to minimize the toxicity and side effects of melanoma treatment, it is important to identify drug candidates that have strong anti-cancer activity and fewer side effects. Lobaric acid is a small molecule that has been found to have significant anti-cancer effects on various types of cancer cells.

Methods: The study aimed to investigate the effects of lobaric acid on human melanoma cell lines (A-375, MDA-MB-435, G-361, and WM-115) and normal human epidermal melanocyte cells. The study also examined the regulation of cell cycle and apoptosis, as well as the gene expression level of apoptosis-related genes and regulatory proteins to induce apoptosis in melanoma cells.

Results: The study suggests that lobaric acid may have an effect on the proliferation of A-375 melanoma cells, with results indicating a dose- and time-dependent manner. Additionally, the study found that the expression levels of 70 target genes out of 88 apoptosis- related genes in the primary apoptosis library panel were obtained. Out of these, 54 genes showed an increase in expression levels, while 16 genes showed a decrease. Moreover, it has been determined that the levels of apoptosis-related proteins, such as Casp3, Casp7, Casp9, and PARP, were increased. The results suggest that lobaric acid induces apoptosis through the extrinsic pathway by upregulating the expression of Caspases and PARP.

Conclusion: The findings of this study provided a strong basis for the use of lobaric acid as a potential therapeutic agent in the treatment of melanoma.

Neuroblastoma (NB) is a rare embryonal neuroendocrine tumor that primarily affects children aged 5 years old or younger. In advanced stages, NB requires a multifaceted treatment approach, including a combination of surgery, chemo, and radiation therapy. However, high-risk NB is still associated with poor prognosis, long-term side effects, and a high chance of relapse. To counter the drawbacks of conventional treatments, the antitumor properties of natural substances have been extensively studied in recent years. Curcumin (CUR) is a polyphenol of the plants of the Curcuma longa species and is well-known for its potent biological activities, such as antioxidant, anti-inflammatory, and anticancer properties. CUR may function as a potential therapeutic compound in NB cells by decreasing cell viability, proliferation, and migration, while inducing oxidative stress and apoptosis in cancer cells. Different molecular pathways have been suggested for this anti-cancer activity of CUR, such as caspase-3 activation, p53 and Bcl-2 signaling pathways, inhibition of AKT and FOXO3 nuclear translocation, and regulation of the chaperoning system proteins. Despite its favorable effects, CUR faces several challenges in treating cancer, such as low bioavailability and bioactivity. Consequently, recent studies have focused on the development of CUR nanoformulations and new drug delivery systems, aiming to overcome these barriers. This review provides an updated summary of the recent literature regarding CUR's protective role in NB and the potential underlying mechanisms. In conclusion, CUR and its nanoformulations show great potential for NB management, and we suggest additional well-designed basic and preclinical studies to explore CUR's efficiency in detail, especially its therapeutic effectiveness in humans.

This study discusses the chemical perspectives of the [18F]F-PSMA probe, a pivotal tool in prostate cancer imaging. [18F]Fluorine, a positron emitter with a half-life of 109.8 minutes, is produced in a cyclotron by bombarding [18O]-enriched targets with protons. The chemistry of this isotope parallels that of stable fluorine, facilitating its use in positron emission tomography (PET). The synthesis of [18F]F-PSMA involves a nucleophilic substitution (SN1) reaction, where [18F]fluoride ion replaces a leaving group in the precursor molecule. Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer cells, making it a crucial target for imaging. PSMA-targeted radioligands, such as [68Ga]Ga-PSMA-11, [18F]F-DCFPyL, and [99mTc]Tc-PSMA-I&S, bind to the extracellular domain of PSMA, enabling precise imaging. The design of PSMA radiotracers incorporates specific targeting moieties, functional groups for radiolabeling, and linkers to maintain binding affinity and pharmacokinetics. Common linkers include aliphatic, aromatic, peptide-based, and polyethylene glycol structures, while functional groups like tosylate and PyTFP are used for efficient [18F]fluorination. This review aims to elucidate the main linker and reactions in order to optimize these components to improve imaging sensitivity and specificity in detecting prostate cancer.

Introduction: Gastric cancer (GC) is the fifth most common cancer globally, and the relationship between type 2 diabetes mellitus (T2DM) and cancer risk remains controversial.

Methods: We performed Mendelian randomization (MR) analysis using publicly available GWAS data to assess the causal relationship between T2DM and GC, validated by heterogeneity and pleiotropy analyses. Transcriptomic data from TCGA and GEO were analyzed to identify common differentially expressed genes (DEGs). Weighted gene co-- expression network analysis (WGCNA) was used to construct a prognostic risk model. Drug sensitivity and immune infiltration were evaluated using GDSC and ImmuCellAI, respectively. Additionally, gene mutation analysis was conducted using TCGA data.

Results: The Mendelian randomization analysis revealed a causal relationship between T2DM and GC at the genetic level. Specifically, the causal effect of T2DM on GC was estimated with an odds ratio (OR) of 1.32 (95% CI: 1.12-1.56), while the reverse causal effect of GC on T2DM was estimated at an OR of 0.78 (95% CI: 0.67-0.91). Sensitivity analyses, including Cochran's Q test and the leave-one-out test, confirmed the robustness of these findings. We constructed a prognostic risk score consisting of three T2DM-related genes (CST2, PSAPL1, and C4orf48) based on transcriptome data analysis. Patients with high-risk scores exhibited significantly worse overall survival (OS) (p < 0.05). Cox regression analysis further confirmed the independent predictive value of the risk score for GC prognosis. Our predictive model demonstrated good performance, with an AUC of 0.786 in the training set and 0.757 in the validation set. Gene enrichment analysis indicated that the genes shared between T2DM and GC were associated with inflammatory response, immune response, and metabolic pathways. Tumor immune microenvironment analysis suggested that immune evasion mechanisms may play a key role in developing GC in patients with coexisting T2DM.

Conclusion: T2DM is associated with reduced GC risk. The risk score and model may help guide GC prognosis and management.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative brain disorder, primarily affecting the elderly. Its socio-economic impact and mortality rate are alarming, necessitating innovative approaches to drug discovery. Unlike single-target diseases, Alzheimer's multifactorial nature makes single-target approaches less effective. To address this challenge, researchers are turning to drug design strategies targeting multiple disease pathways simultaneously. This approach has led to the promising identification of dual or multiple-target inhibitors, offering new perspectives for improving disease management. Computer-Aided Drug Design (CADD) such as virtual screening, docking, QSAR, molecular dynamics, ADMET prediction, etc., are valuable tools for designing and identifying new multi target directed ligands (MTDLs). These methods enable efficient screening of extensive compound libraries and accurate prediction of pharmacokinetic profiles, optimizing development costs and time. Challenges such as model accuracy, simulation complexity, and data integration persist. Addressing these issues requires advances in in silico modeling, high-performance computing, and experimental validation. In this regard, this review highlights recent advances using various computational methods to screen and identify new candidate compounds containing different heterocyclic motifs that could serve as potential bases for designing ligands targeting multiple targets for Alzheimer's disease.

Targeted therapy for colorectal cancer (CRC) appears to have great potential with lipid nanoparticles (LNPs). The advances in LNP-based techniques, such as liposomes, exosomes, micelles, solid lipid nanoparticles (SLNs), nano-cubosomes, and plant- derived LNPs (PDLNPs), are explored in detail in this thorough review. Every platform provides distinct advantages: liposomes enable precise drug release and improved delivery; exosomes function as organic nanocarriers for focused treatment; SLNs offer greater stability; micelles enhance drug solubility and resistance; nano-cubosomes tackle low bioavailability; and PDLNPs offer biocompatible substitutes. The mechanisms, benefits, drawbacks, and therapeutic potential of these LNP platforms in the treatment of colorectal cancer are highlighted in the review. The review highlights how crucial it is to use these technologies for efficient CRC management and looks at potential future developments for them. The controlled release properties of liposomes and solid liposome nanoparticles (SLNs) improve the stability and bioavailability of medicinal compounds. On the other hand, exosomes and micelles provide answers for medication resistance and solubility issues, respectively. Novel strategies for resolving bioavailability problems and enhancing biocompatibility include nano-cubosomes and PDLNPs. These LNP-based systems are promising in clinical applications for boosting therapeutic efficacy, decreasing systemic toxicity, and facilitating tailored drug delivery. By incorporating these nanotechnologies into CRC treatment plans, present therapeutic approaches may be completely changed, and more individualized and efficient treatment choices may be provided. To completely comprehend the advantages and drawbacks of these LNP systems in therapeutic settings, as well as to and optimize them, more study is recommended by the review. Treatment for colorectal cancer may be much improved in the future thanks to developments in LNP-based drug delivery systems. These technologies hold great promise for improving patient outcomes and advancing the field of oncology by tackling important issues related to medication delivery and bioavailability.

Background: Resveratrol (RES) is a phytochemical bioactive compound with suggested therapeutic benefits.

Objective: The current work aimed to evaluate the anti-inflammatory effect of RES against palmitate (PA) induced lipotoxicity in raw 264.7 macrophages cell line.

Methods: The cells viability was assessed by lactate dehydrogenase assay. Then the effects of RES and PA on nitric oxide (NO), triglyceride (TG) content, and cytokines release were studied. The effect of RES and PA on the treated cells bioenergetics and redox status was evaluated via different assays Results: The results showed that at doses of 10 and 20μM, RES dramatically increased the vitality of PA-exposed macrophages with dramatic significant decrease in the release the proinflammatory cytokines TNF-α, MHGB-1, IL-1β, and IL-6 and their coding genes expression with marked improvement in the cells phagocytic capacity. In addition, RES dramatically lowered the levels of NO and TG in PA-stimulated macrophages. In addition, PA markedly decreased mitochondrial complexes I and III activities with decreased mitochondrial membrane potential and lowered ATP production with induction of oxidative stress. RES was shown to mitigate the effect of PA on macrophages bioenergetics and the oxidative damage and counteracted PA effect on genes linked to oxidative damage, such as Nrf2, Ho-1, NF-κB p65, SOD1, and SOD2.

Conclusion: RES could reduce PA-induced lipotoxicity in macrophages via enhancing their viability and counteracting the excess release of cytokines through alleviating PAinduced bioenergetic disruption and oxidative damage with a suggested positive impact of RES on obesity related illnesses caused by triggered cellular inflammation.

Introduction: Elevated glucose can have a detrimental effect on the function and healing process of periodontal cells in inflammatory conditions. Hesperidin (HPN), a bioflavonoid found abundantly in citrus fruits, has numerous biological benefits, including regenerative and anti-inflammatory properties. The current in-vitro study aimed to assess the impact of HPN on the proliferation, wound healing, and functionality of periodontal cells in optimal and elevated glucose conditions.

Methods: Human periodontal ligament cells (HPDLCs) were cultured in optimal glucose (1g/L) (OG) and high glucose (4.5 g/L) (HG) conditions. XTT, wound healing, ALP, and calcium release assays were conducted with or without HPN in the culture media.

Results: The statistical analysis revealed that adding different concentrations of HPN (2, 4, 10, or 100 μM) had no significant effect on the viability of HPDLCs under both OG (p=0.436) and HG conditions (p=0.162) compared to the control. However, in the HG condition, the addition of 100 μM HPN resulted in a statistically significant increase in wound closure (p=0.003). Furthermore, in the HG condition, the addition of 100 μM HPN significantly increased ALP activity in the OS- media (p=0.001) and significantly increased calcium release within the OS+ media (p=0.016).

Conclusion: The findings of this study suggest that HPN provides beneficial effects, facilitating repair and mineralization in HPDLCs under HG conditions.